1. Field of the Invention
The present invention relates to a pulsed signal generator for biomedical applications. In particular, the present invention relates to a simple, compact pulsed signal generator for use in stimulation of fracture healing, treatment of osteoporosis, and other applications.
2. Discussion of Background
Several million Americans suffer broken bones every year; many of them having multiple fractures. Bone fractures are a major source of pain, inconvenience, expense, lost time and diminished workplace productivity. Even in a young, healthy patient, many fractures must be immobilized for six weeks or longer while healing takes place; after the cast or other fixation device is removed, the patient's activities must be restricted until the newly-healed bone regains its full strength. In the elderly population and in persons with poor health, malnutrition, or medical conditions such as diabetes that impact normal healing processes, fractures may heal slowly or not at all resulting in what are known as "nonunions."
Fracture healing, and in many cases the healing of other tissues as well, can be accelerated by the application of suitably-chosen, low-level electrical signals resembling those naturally present in tissues subjected to normal environmental levels of mechanical stress. Typical methods of doing this, however, require apparatus which is expensive, bulky and inconvenient to use, and/or requires surgical implantation.
Human bone is a combination of organic and mineral components. The chief mineral constituent of bone is hydroxyapatite, a complex calcium phosphate (Ca.sub.5 (PO.sub.4).sub.3 OH) in crystalline form. Like quartz, hydroxyapatite is piezoelectric: that is, it generates an electric charge or current when mechanically stressed. Collagen, the tough fibrous protein which surrounds the hydroxyapatite crystals and binds them together, is also piezoelectric.
Normally the electric signals generated by bone (sometimes called "bone talk") are weak and of relatively low frequency, replicating the pattern of mechanical forces placed on the bones from outside. When bone is strongly stressed, however, the hydroxyapatite crystals eventually start to slip little by little past each other and higher-frequency signals, having a characteristic pattern of sharp pulses separated by intervals of no signal, begin to appear. These signals arise from a mechanism much like that which creates the noise of a creaking floor: the wood surfaces or fibers alternately stick together and then, when the applied force becomes too great, give way abruptly and create a pulse of sound. Many such pulses in rapid succession make up the creaking sound we hear when walking across a creaking floor. A sensitive microphone can pick up the audio signals emitted by stressed bone; since any piezoelectric material is itself a microphone of sorts, the same pattern also appears as an electrical signal.
Osteoblasts, the cells within bone which secrete and deposit hydroxyapatite, are very sensitive to electric signals of this type and respond by forming larger amounts of hydroxyapatite. This creates a feedback mechanism, causing the bone to be strengthened automatically at points of stress concentration where the signals tend to be strongest. When the feedback loop breaks down-as when the bone receives little stress, when the diet is calcium-deficient, or when disease makes the cells less sensitive-osteoporosis can result. By the same token, restoring or strengthening the "bone talk" electrical signals can reverse or prevent the condition.
When a bone is fractured, current medical practice is first to "set" the bone with the fractured end surfaces close together, and then to immobilize it with a cast, splint, or fixator (internal or external) until the fracture heals. This practice has advantages and disadvantages. One advantage is that, since the fractured surfaces are close together, little bone tissue is needed to close the gap. On the other hand, the immobilized section of bone is exposed to little or no stress, next to no "bone talk" is generated, and thus, once again, the feedback loop which governs formation of new bone is broken. As a result, the osteoblasts in the vicinity of the fracture work at reduced capacity and the fracture takes a long time to heal. In all too many cases, complete healing never takes place and the fracture becomes a permanent nonunion.
It has long been known that the application of electric currents can restore healing (of nonunions) and speed bone growth and repair (of normal fractures). In the mid-1960s, C. A. L. Bassett and others measured the weak electrical signals generated by bone itself, analyzed and reproduced those signals artificially, and used them to reverse osteoporosis or aid in the healing of fractured bones.
A waveform which has been found effective is shown schematically in FIG. 1, where a line 10 represents the waveform on a short time scale, a line 12 represents the same waveform on a longer time scale, an interval 14 represents a peak voltage or current amplitude, and intervals 16, 18, 20, and 22 represent the timing between specific transitions. Alternate repetition of intervals 16 and 18 generates pulse bursts 24, each having a length 20 and separated by an interval 22 wherein the signal undergoes no transitions. For example, interval 16 may be about 200 microseconds, interval 18 about 28 microseconds, interval 20 about 5 milliseconds, and interval 22 about 62 milliseconds so that pulse bursts 24 recur at a frequency of about 15 Hertz.
The precise characteristics of the signal depicted in FIG. 1 are not at all critical. Indeed, the characteristics of naturally-occurring bone electrical signals depend on several factors, including the type, size and mineral density of the bone involved, the amount of stress and its rate of application, and probably on many other factors as well. Hence, osteoblasts are believed to be able to respond to a wide range of electrical signals. Typical laboratory studies of the effects of applied electrical signals on bone growth have been performed using signals that are approximately of the form shown in FIG. 1, with intervals 16, 18, 20 and 22 each within about a factor of five (i.e., from about 20% to about 500%) of the values given above. Some studies have utilized continuous pulse trains where interval 18 is reduced to zero. For example, a continuous pulse train 26 is shown in FIG. 2, may have an interval 20 of about 380 microseconds and an interval 22 of about 13 milliseconds, for a repetition rate of 75 Hertz (FIG. 2). Signals such as pulse train 26 have been used widely and successfully in treating osteoporosis.
While it was initially thought that signals applied from outside the body would have to be relatively strong to be biologically active, it now appears that a threshold effect is involved. Signals at levels comparable to those of normal "bone talk" (that is, resembling the signal shown in FIG. 1 with interval 14 representing a few microamperes per square centimeter of tissue cross-section) can increase the rate of healing in fresh fractures by as much as 100% and can restimulate healing in up to 80% of long-standing nonunions. Surprisingly, signals of like form but greater amplitude (as much as thousands of times more powerful) provide no greater benefit than the weaker signals, and often less. This relationship is shown in FIG. 3, where a line 28 represents the level of benefit at various signal intensities, where "benefit" refers to observable increases in healing (or normal fractures) or stimulation of healing (of nonunions). A peak applied voltage 30 typically falls somewhere around ten microamperes per square centimeter, and a crossover point 32 at about a hundred times this value. Beyond point 32, the signal slows healing rates rather than increasing them, and may itself cause further injury.
DC signals may also be useful, but are undesirable at almost any level since they can cause electrolytic damage to tissues through which they pass and, if too strong or of the wrong polarity, can actually cause bone loss.
Healing is a cellular process triggered by the occurrence of an injury (for purposes of this specification, the terms "wound" and "injury" refer to tissue damage or loss of any kind, including but not limited to cuts, incisions, abrasions, lacerations, fractures, contusions, burns, and so forth). In general, the progress of healing in any injured tissue, whether bone or a soft tissue such as skin or muscle, takes place in several well-defined stages of cell migration and proliferation. These are shown schematically in FIG. 4. Here, lines 40 through 44 represent the populations of various cell types involved in repair, while lines 46 and 48 show the progress of the repair through tissue rebuilding.
Neutrophils and monocytes, indicated by lines 40 and 42, respectively, are elements of the immune system which clean away damaged cells and destroy foreign organisms such as bacteria (if present) at the injury site. Their activity, which typically peaks from the second to the fourth day after the injury, corresponds to the inflammation phase of healing.
Fibroblasts, another type of cell indicated by line 44, then begin the repair process proper: building a framework of collagen, the same tough protein which binds the mineral components of bone together, and to which other cell types then adhere to form the rebuilt tissue. At about the same time, the number of capillaries, indicated by line 46, increases to supply needed materials for tissue rebuilding. The fibroblast population usually peaks around the sixth day after the injury, when the most rapid collagen formation is taking place (as shown by line 48). Once the basic framework is laid down, typically around the eighth day after the injury, the fibroblast population decreases. Collagen is deposited at a slower rate for several weeks more, while other types of cells continue to migrate into the injury site and proliferate to form a complete tissue.
Increases in the rate of healing have also been observed in soft-tissue injuries, such as nerve damage and skin wounds, when electrical signals were applied experimentally to the injured tissue or were being used to treat nearby bone. Hence, it seems likely that healing processes are naturally stimulated by "bone talk"-type electrical signals or by the piezoelectric response of other body tissues to environmental stress.